Faculty

Jeffrey A. Lewis

All organisms must endure diverse environmental stresses during their lifetime. Our lab seeks to understand how microbes adapt and even thrive in the face of various environmental assaults. Microbial stress responses are remarkably complex, coordinating multiple levels of sensing, signal transduction, and global regulatory networks. Thus, stress research feeds into nearly all aspects of cell biology, with implications for human disease, microbial pathogenesis, and the evolution of regulatory networks.

Our group studies stress responses through the perspective of natural variation. Inarguably, model organisms have provided fundamental insights into basic biology. However, most of our knowledge derives from a small number of domesticated lines—we lack a detailed knowledge of the ecology and phenotypic diversity of different individuals within the same microbial species. With the advent of genomic technologies, we are now uniquely poised to perform comparative genomic studies on wild microbial strains. We use these powerful new approaches, as well as classical genetics and biochemistry, to identify stress regulatory pathways, non-coding RNAs, and genes with previously unknown functions.

Our lab studies how microbes sense and respond to various environmental assaults. We take advantage of natural variation between wild microbial isolates to understand how the environment and evolution shape the stress responses and physiology of microorganisms. We use a combination of genomic, genetic, and biochemical approaches to study the following areas:

Natural variation in yeast stress responses

Understanding how gene-environment interactions determine phenotype is a fundamental goal in genetics. For many traits, including several of clinical importance, this interplay is complex—multiple genes interact with environmental factors in a combinatorial manner. We use yeast stress responses as a model to study gene-environment interactions, gene regulatory divergence, and the genetics of complex traits. We have performed expression quantitative trait loci (eQTL) mapping of the yeast ethanol response, which is providing a wealth of insights into the genetic source of regulatory divergence between wild and laboratory yeast strains. We are currently using bulk-segregant analysis to identify connections between ethanol signaling and ethanol-mediated cross-protection against other stresses.

Role of post-translational protein modifications in response to stress

Recent evidence suggests that the function of stress-activated gene expression is not to survive the initial insult, but instead protects against an impending severe stress. Consistent will this idea, maximal gene expression changes can take over half an hour—far too long a timescale to provide acute protection from stress. In contrast, post-translational protein modifications (PTMs) happen on the order of seconds, allowing for rapid regulation in response to acute stress. In support of a role for PTMs in the immediate response to stress is the observation that numerous stress defense proteins have PTMs. How these PTMs affect stress defense remains mostly unknown. We are using biochemical, genetic, and molecular approaches to understand the physiological role of PTMs, namely acetylation, during the acute response to stress. We are also using quantitative genetics (QTL mapping) to explore the genetic basis of natural variation in PTMs in wild and laboratory yeast strains. These studies will shed light on potential stress-responsive regulators of PTMs.

Function of stress-regulated non-coding RNAs

Multiple studies have found that a much larger portion of the genome is transcribed than was originally thought. The vast majority of these novel transcripts do not code for proteins. The functions for most of these non-coding (nc) RNAs remain obscure, but many are hypothesized to play regulatory roles. We have identified hundreds of stress-regulated ncRNAs, as well as extensive natural variation in ncRNA expression across different strain backgrounds. We are employing eQTL mapping of ncRNAs to identify novel regulators of ncRNA expression, and to generate and test hypotheses for ncRNA function.

Collaborative Projects

Insights into the domestication of yeast.

In collaboration with Dana Wohlbach at Dickinson College, we are performing laboratory evolution to understand the genomic changes that accompany domestication of yeast.

The response of yeast to extreme pressure and temperature.
In collaboration with Pradeep Kumar at the University of Arkansas, we are working to understand how yeast cells respond and evolve to both high hydrostatic pressures and temperatures, which appear to elicit partially overlapping responses.

Development of genetic tools for marine microbes.
In collaboration with Andy Alverson at the University of Arkansas, we have received funding from the Gordon and Betty Moore Foundation to develop a transformation system and new genetic tools for diatoms.

The impact of fracking on microbial communities.
In collaboration with Marlis Douglas and Michael Douglas, we are determining whether stream biofilm communities are sensitive to the chemical signatures of fracking.